Synthetic approaches towards avibactam and other diazabicyclooctane β-lactamase inhibitors

Peilleron, Laure; Cariou, Kevin

doi:10.1039/c9ob02605c

Cited by 17 publications

(16 citation statements)

References 52 publications

(46 reference statements)

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“…Chiral piperidines, L-glutamic acid, and L-pyroglutamic acid were considered as starting materials and Boc-benzyl-L-glutamate was used to optimize the synthetic process [ 154 ]. Recently, Laure Peilleron and Kevin Cariou have reported the synthesis of avibactam starting from a commercially available chiral oxo-pyrrolidine ( Scheme 10 ) [ 155 ] (Novexel).…”

Section: Marketed and Not Marketed Blesis: Guidelines For Their Synth...mentioning

confidence: 99%

Recommendations to Synthetize Old and New β-Lactamases Inhibitors: A Review to Encourage Further Production

Alfei

Zuccari

2022

Pharmaceuticals

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The increasing emergence of bacteria producing β-lactamases enzymes (BLEs), able to inactivate the available β-lactam antibiotics (BLAs), causing the hydrolytic opening of their β-lactam ring, is one of the global major warnings. According to Ambler classification, BLEs are grouped in serine-BLEs (SBLEs) of class A, C, and D, and metal-BLEs (MBLEs) of class B. A current strategy to restore no longer functioning BLAs consists of associating them to β-lactamase enzymes inhibitors (BLEsIs), which, interacting with BLEs, prevent them hydrolyzing to the associated antibiotic. Worryingly, the inhibitors that are clinically approved are very few and inhibit only most of class A and C SBLEs, leaving several class D and all MBLEs of class B untouched. Numerous non-clinically approved new molecules are in development, which have shown broad and ultra-broad spectrum of action, some of them also being active on the New Delhi metal-β-lactamase-1 (NDM-1), which can hydrolyze all available BLAs except for aztreonam. To not duplicate the existing review concerning this topic, we have herein examined BLEsIs by a chemistry approach. To this end, we have reviewed both the long-established synthesis adopted to prepare the old BLEsIs, those proposed to achieve the BLEsIs that are newly approved, and those recently reported to prepare the most relevant molecules yet in development, which have shown high potency, providing for each synthesis the related reaction scheme.

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Section: Marketed and Not Marketed Blesis: Guidelines For Their Synth...mentioning

confidence: 99%

Recommendations to Synthetize Old and New β-Lactamases Inhibitors: A Review to Encourage Further Production

Alfei

Zuccari

2022

Pharmaceuticals

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“…Since 2012 several new broad-spectrum inhibitors of class A and class C β-lactamases have emerged. Of significant interest, avibactam 8,9 and vaborbactam 10 (Figure 1b) were approved by the FDA for clinical use whilst many of their congeners, in particular diazabicyclooctanes, [11][12][13][14][15] are currently going through preclinical or clinical development. These compounds are mainly able to efficiently inhibit SBLs, including carbapenemases, of class A, C and sometimes D, but generally do not inhibit MBLs (class B).…”

Section: Table Of Contentsmentioning

confidence: 99%

Azetidinimines as a Novel Series of Non-Covalent Broad-Spectrum Inhibitors of β-Lactamases with Submicromolar Activities Against Carbapenemases of Classes A, B and D

Romero¹,

Oueslati²,

Benchekroun³

et al. 2020

Preprint

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The increasingly worrisome situation of antimicrobial resistances has pushed synthetic chemists to design original molecules that can fight these resistances. To do so, inhibiting β-lactamases, one of the main modes of resistance to β-lactam antibiotics, is one of the most sought-after strategies, as recently evidenced by the development and approval of avibactam, relabactam and vaborbactam. Yet molecules able to inhibit simultaneously β-lactamases belonging to different molecular classes remain scarce and currently there is no metallo-β-lactamase inhibitor approved for clinical use. Having recently developed a synthetic methodology to access imino-analogues of β-lactams (Chem. – Eur. J. 2017, 23, 12991,see ref) we decided to evaluate them as potential β-lactamase inhibitors and specifically against carbapenemases, which can hydrolyze and inactivate penicillins, cephalosporins and carbapenems. Herein we eport our findings that show that our newly developed family of molecules are indeed excellent β-lactamase inhibitors and that our lead compound can inhibit NDM-1 (0.1 µM), KPC-2 (0.4 µM), and OXA-48 (0.6 µM) even though these three enzymes belong to three different molecular classes of carbapenemases. This lead compound also inhibits the ESBL CTX-M-15 and the cephalosporinase CMY-2, it is metabolically stable, and can repotentiate imipenem against a resistant strain of Escherichia coli expressing NDM-1.<br><br><br>

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“…The mechanism of action of these secondgeneration inhibitors is mostly studied using avibactam. It has been realized that avibactam forms a reversible intermediate with the substrate enzyme for its deactivation [47,48]. This is in contrast to its predecessors, clavulanic acid [49], sulbactam, and tazobactam [50], which were suicidal in terms of their mechanism [51] (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

“…Alternative process development was started by Merck, and the first synthetic route was disclosed in 2009. The optimized development process for avibactam and relebactam has been recently reviewed in detail [48]. The reviews describe the synthetic processes and associated alterations over time in detail and further discuss other avibactam derivatives such as triazole analogues, nacubactam, zidebactam, durlobactam, NXL-105, IID572, ETX2514, and cyclopropane-fused derivatives, etc.…”

Section: Introductionmentioning

confidence: 99%

Recent Developments to Cope the Antibacterial Resistance via β-Lactamase Inhibition

et al. 2022

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Antibacterial resistance towards the β-lactam (BL) drugs is now ubiquitous, and there is a major global health concern associated with the emergence of new β-lactamases (BLAs) as the primary cause of resistance. In addition to the development of new antibacterial drugs, β-lactamase inhibition is an alternative modality that can be implemented to tackle this resistance channel. This strategy has successfully revitalized the efficacy of a number of otherwise obsolete BLs since the discovery of the first β-lactamase inhibitor (BLI), clavulanic acid. Over the years, β-lactamase inhibition research has grown, leading to the introduction of new synthetic inhibitors, and a few are currently in clinical trials. Of note, the 1, 6-diazabicyclo [3,2,1]octan-7-one (DBO) scaffold gained the attention of researchers around the world, which finally culminated in the approval of two BLIs, avibactam and relebactam, which can successfully inhibit Ambler class A, C, and D β-lactamases. Boronic acids have shown promise in coping with Ambler class B β-lactamases in recent research, in addition to classes A, C, and D with the clinical use of vaborbactam. This review focuses on the further developments in the synthetic strategies using DBO as well as boronic acid derivatives. In addition, various other potential serine- and metallo- β-lactamases inhibitors that have been developed in last few years are discussed briefly as well. Furthermore, binding interactions of the representative inhibitors have been discussed based on the crystal structure data of inhibitor-enzyme complex, published in the literature.

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Synthetic approaches towards avibactam and other diazabicyclooctane β-lactamase inhibitors

Abstract: The synthetic strategies to obtain avibactam and other diazabicyclooctane β-lactamase inhibitors such as ETX2514 are presented.

Cited by 17 publications

References 52 publications

Recommendations to Synthetize Old and New β-Lactamases Inhibitors: A Review to Encourage Further Production

Recommendations to Synthetize Old and New β-Lactamases Inhibitors: A Review to Encourage Further Production

Azetidinimines as a Novel Series of Non-Covalent Broad-Spectrum Inhibitors of β-Lactamases with Submicromolar Activities Against Carbapenemases of Classes A, B and D

Recent Developments to Cope the Antibacterial Resistance via β-Lactamase Inhibition

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